Silent Corticotroph Adenomas Research Articles

Transcriptome and methylome analysis reveals three cellular origins of pituitary tumors

Pituitary adenomas (PA) are the second most common intracranial tumors. These neoplasms are classified according to the hormone they produce. The majority of PA occur sporadically, and their molecular pathogenesis is incompletely understood. The present transcriptomic and methylomic analysis of PA revealed that they segregate into three molecular clusters according to the transcription factor driving their terminal differentiation. First cluster, driven by NR5A1, consists of clinically non-functioning PA (CNFPA), comprising gonadotrophinomas and null cell; the second cluster consists of clinically evident ACTH adenomas and silent corticotroph adenomas, driven by TBX19; and the third, POU1F1-driven TSH-, PRL- and GH-adenomas, segregated together. Genes such as CACNA2D4, EPHA4 and SLIT1, were upregulated in each of these three clusters, respectively. Pathway enrichment analysis revealed specific alterations of these clusters: calcium signaling pathway in CNFPA; renin-angiotensin system for ACTH-adenomas and fatty acid metabolism for the TSH-, PRL-, GH-cluster. Non-tumoral pituitary scRNAseq data confirmed that this clustering also occurs in normal cytodifferentiation. Deconvolution analysis identify potential mononuclear cell infiltrate in PA consists of dendritic, NK and mast cells. Our results are consistent with a divergent origin of PA, which segregate into three clusters that depend on the specific transcription factors driving late pituitary cytodifferentiation.

The Role of T-box Transcription Factor in a Pituitary Adenoma Diagnostic Algorithm.

We previously examined pituitary adenomas with immunohistochemical (IHC) stains for steroidogenic factor 1, Pit-1, anterior pituitary hormones, cytokeratin CAM 5.2, and the α-subunit of human chorionic gonadotropin and found that a screening panel comprising stains for steroidogenic factor 1, Pit-1, and adrenocorticotropic hormone successfully classified most cases and reduced the overall number of stains required. To examine the potential role of IHC stain for T-box transcription factor (Tpit) in the classification of our series of pituitary adenomas and to update our screening panel as necessary. We collected 157 pituitary adenomas from 2 institutions and included these in tissue microarrays. Immunostains for Tpit were scored in a blinded fashion using the Allred system. Adenomas were assigned to a gold standard class based on IHC pattern followed by application of available clinical and serologic information. Test characteristics were calculated. Correlation analyses, cluster analyses, and classification tree analyses were used to see whether IHC staining patterns reliably reflected adenoma class. Of the cases collected, 147 (93.6%) had sufficient material for Tpit analysis. IHC stain for Tpit identified 8 null cell adenomas (all nonfunctioning clinically) as silent corticotrophs; Tpit stains showed better sensitivity, specificity, positive predictive value, and negative predictive value than IHC for adrenocorticotropic hormone and cytokeratin CAM 5.2. Correlation analyses continued to show the expected relationships among IHC stains. Cluster analyses showed grouping of adenomas into clinically consistent groups. Classification tree analysis underscored the central role of transcription factor IHC stains, including Tpit, in adenoma classification. Substitution of Tpit stain for the adrenocorticotropic hormone stain improves our prior algorithm by reducing the number of false-negatives and false-positives. As a result, fewer adenomas are classified as null cell adenoma, and more adenomas are classified as silent corticotroph adenoma.

Clinical, Laboratory, and Treatment Profiles of Silent Corticotroph Adenomas That Have Transformed to the Functional Type: A Case Series With a Literature Review.

Purpose: Silent corticotroph adenoma (SCA) is clinically non-functional pituitary adenoma with expression of corticotropin or Tpit. To further understand the characteristics of this rare type of SCA transforming to a functional SCA, we retrospectively reviewed SCAs that converted to typical Cushing's syndrome at a tertiary medical center and the relevant literature.Methods: Patients were identified based on the diagnosis of pituitary adenoma without symptoms of hypercortisolism at the initial visit with positive Immunohistochemical (IHC) staining for corticotropin or Tpit after surgery and subsequent transformation to functional SCAs during the follow-up period from March 1990 to January 2020 at Peking Union Medical College Hospital and in the literature. The characteristics of the clinical manifestations, biochemical results, imaging findings, pathology findings and outcome were analyzed.Results: Altogether, 16 patients were included in the study with an average age of 42.0 ± 12.48 (18–65) years at the first visit. Females were slightly predominant (F:M = 1.3:1). The median time of conversion from the nonfunctional to the functional type was 30 (13.0, 68.3) months. Once a functional SCA developed, the adrenocorticotropic hormone (ACTH) level and 24-h urine free cortisol were increased 3.8- (2.6, 12.9) and 5.3- (2.6, 19.3) fold, respectively, above the normal range. Approximately 50% of the patients had macrocystic changes on pituitary MRI. All 16 patients experienced 1–5 surgeries with a median of 2.5 (2.0, 4.0) surgeries. The proportion of patients with Ki-67 ≥ 3% increased from 22.2% (2/9) at the beginning to 50% (7/14) at the time of functional SCA diagnosis. Thirteen patients received radiotherapy, and 4 patients (30.8%) achieved remission. Four patients with refractory functional SCAs received temozolomide treatment with the normalization of cortisol in 4 cases and reduced tumor volume in 3 cases.Conclusion: In this study, all cases that transformed to functional SCAs were macroadenomas. Hypercortisolism was more severe in functional SCA patients. The tumors tended to have frequent recurrence and were highly invasive. Temozolomide could be a promising treatment for refractory functional SCA cases. Long-term follow-up is needed for nonfunctional SCAs since some cases have the potential to transform to clinical Cushing's syndrome.

UPLC-MS/MS-based Lipidomic Profiles Revealed Aberrant Lipids Associated with Invasiveness of Silent Corticotroph Adenoma.

The accumulation of aberrant lipids and abnormal lipid metabolism in silent corticotroph adenomas (SCAs) could contribute to changes in clinical phenotypes, especially sphenoid sinus invasion. To systematically investigate lipidomic and transcriptomic alterations associated with invasiveness and their potential molecular mechanisms in SCAs and to provide candidate biomarkers for predicting invasiveness and novel treatment options for invasive SCAs by targeting lipids. Fifty-four SCAs (34 invasive/20 noninvasive) were subjected to lipidomic analysis based on ultraperformance liquid chromatography mass spectrometry, and 42 clinically nonfunctioning pituitary adenomas (23 invasive/19 noninvasive) were subjected to transcriptomic analysis. Differential analysis was performed to determine differential lipids and genes between invasive and noninvasive tumors. A functionally connected network was constructed with the molecular pathways as cores. Multiple machine learning methods were applied to identify the most critical lipids, which were further used to construct a lipidomic signature to predict invasive SCAs by multivariate logistic regression, and its performance was evaluated by receiver operating characteristic analysis. Twenty-eight differential lipids were identified, and a functionally connected network was constructed with 2 lipids, 17 genes, and 4 molecular pathways. Connectivity Map (CMap) analysis further revealed 32 potential drugs targeting 4 genes and related pathways. The 4 most critical lipids were identified as risk factors contributing to the invasive phenotype. A lipidomic signature was constructed and showed excellent performance in discriminating invasive and noninvasive SCAs. The lipidomic signature could serve as a promising predictor for the invasive SCA phenotype and provide potential therapeutic targets for SCAs.

Neuroimaging of aggressive pituitary tumors.

Aggresssive pituitary tumors are defined as radiologically invasive, exhibiting a rapid growth and a poor response to the medical and surgical treatment options. The role of magnetic resonance imaging (MRI) is fundamental to assess tumor aggressiveness before surgical exploration. Distinction between cavernous sinus invasion and cavernous sinus compression is often challenging and cannot be solved always by using the Knosp criteria. Ideally, T2W images demonstrating the ruptured internal dural wall of cavernous sinus is the ultimate proof of cavernous sinus invasion. Subtle tumor volume increase in a short time can be shown when sequential MR images are rigorously replicable. A microcystic pattern observed on T2W images frequently reflects a potentially aggressive tumor as observed in silent corticotroph pituitary adenomas.

SAT-301 Relationship Between Clinicopathological Aspects and MSH6/MSH2 and PD-L1 Expressions in Clinically Nonfunctioning Pituitary Adenomas

Introduction: Mismatch repair (MMR) genes are associated with the MMR mechanism that corrects DNA polymerase misincorporation errors. We analyzed the aggressive pituitary adenomas (PAs) associated with Lynch syndrome due to germline mutation in the MMR gene. Reduced expression of MMR genes mutS homologs 6/2 (MSH6/2) directly promotes PA growth (1, 2). MMR gene expression and programmed cell death 1 ligand 1 (PD-L1) expression are involved in tumor immunity with immune checkpoint inhibitors, but the direct association in PAs is not fully understood. Hypothesis and Objectives: MSH6/2 and PD-L1 expression could affect PA proliferation and invasion by pathological classification of nonfunctioning (NF) PAs because the proliferation and invasiveness differ depending on the PA histological subtype. In this study, we therefore analyzed the correlation between MSH6/2 and PD-L1 mRNA expression levels and clinicopathological factors related to tumor proliferation using human NFPAs. Experimental Design: We performed immunohistochemistry to classify the NFPAs into gonadotroph adenomas (GAs), silent corticotroph adenomas (SCAs), null cell adenomas (NCAs) and pituitary transcription factor 1 (PIT1) lineage PAs according to 2017 WHO classifications. Quantitative analyses were by real-time PCR to detect MSH6/2 and PD-L1 mRNA expressions in NFPAs (n = 89). We also performed statistical analyses of the expressions and clinicopathological factors such as Knosp Grade and histological subtypes. We investigated the effect of MSH6 knockout on cell proliferation and PD-L1 expression in AtT-20ins cells. Major Results: MSH6/2 expression was positively associated with PD-L1 expression. MSH6/2 and PD-L1 expressions are significantly lower in invasive NFPAs with Knosp Grade 3–4 or recurrence than in non-invasive NFPAs with Knosp Grade 1–2. Their expression is significantly lower in SCAs and NCAs than in GAs. Although MSH6/2 expression also tends to be lower, the PD-L1 expression tends to be higher in PIT1 lineage PAs, which is unlike SCAs and NCAs. MSH6 knockout in AtT-20ins significantly decreased PD-L1 expression with cell proliferation promotion. Interpretation of results and Conclusion: MSH6/2 and PD-L1 expressions of SCAs, NCAs, and PIT1 lineage PAs compared to GAs were thought to contribute to their clinically aggressive behaviors. The molecular mechanism of the difference in clinical features of NFPAs was partially elucidated. In particular, reduced expressions of MSH6/2 were thought to be useful for predicting the proliferation and invasiveness of NFPAs.

Nonfunctioning pituitary adenomas in pediatric and adolescent patients: a clinical analysis of a series of 14 patients.

Nonfunctional pituitary adenomas (NFPAs) in pediatric and adolescent age are extremely rare. This study aimed to report a series of 14 pediatric and adolescent NFPAs to assist in its clinical management. A total of 14 consecutive patients pathologically diagnosed with NFPAs (age ≤ 20years) were retrospectively examined, and the clinical data were analyzed. NFPA is uncommon in pediatric and adolescent patients (0.4%). The most common clinical symptoms were a headache (6/14, 42.9%) and visual loss (4/14, 28.6%). Ten patients (71.4%) had preoperative hypopituitarism. All patients were diagnosed with macroadenoma including 8 (57.1%) invasive tumors, and the average tumor diameter was 2.8cm. All patients underwent transsphenoidal surgery, and a near-total resection was achieved in nine (64.3%) patients. Postoperative visual acuity improved in three patients (75%). The results of immunohistochemistry showed 6 silent plurihormonal adenomas (42.9%), 3 null cell adenomas (21.4%), 3 silent lactotroph adenomas (21.4%), 1 silent gonadotroph adenoma (7.1%) and 1 silent corticotroph adenoma (7.1%). The mean follow-up was 54.8months, and five patients had tumor recurrence. Tumors with Ki-67 ≧ 2% (28.6%) showed higher recurrence rate than those with lower index (P = 0.001). Two patients received secondary surgery and radiation for recurrent tumors suffered from panhypopituitarism. Pediatric and adolescent NFPA is clinically rare, and shows potential invasiveness. The silent plurihormonal adenoma is the most frequent phenotype. Transsphenoidal surgery is as safe and effective as in adults. However, individualized care and teamwork of neurosurgeons, pediatricians, endocrinologists, and radiation oncologists are important, especially for recurrent diseases.

MSH6/2 and PD-L1 Expressions Are Associated with Tumor Growth and Invasiveness in Silent Pituitary Adenoma Subtypes.

Mismatch repair genes mutS homologs 6/2 (MSH6/2) expressions are involved in tumor growth and programmed cell death 1 ligand 1 (PD-L1) expression in tumor immunity, but the direct association with pituitary adenomas (PAs) is not well understood. We aimed to clarify the effects of MSH6/2 and PD-L1 expression on tumor proliferation and invasiveness in nonfunctioning (NF) PAs. We performed immunohistochemistry to classify the NFPAs into gonadotroph adenoma (GAs), silent corticotroph adenomas (SCAs), null cell adenoma (NCAs), and pituitary transcription factor 1 (PIT1) lineage PAs. We evaluated MSH6/2 and PD-L1 mRNA expressions in NFPAs by real-time PCR (n = 73), and statistically analyzed the expressions and clinicopathological factors. We also investigated the effect of MSH6 knockout on PD-L1 expression in AtT-20ins and GH3. MSH6/2 expressions were significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. MSH6/2 expressions were positively associated with PD-L1 expression. PD-L1 expression was significantly lower in invasive NFPAs than in non-invasive NFPAs, and lower in SCAs and NCAs than in GAs. Although MSH6/2 expressions also tended to be lower in PIT1 lineage PAs than in GAs, PIT1 lineage PAs expressed PD-L1 equivalently to GA, which was unlike SCAs and NCAs. MSH6 knockout in AtT-20ins and GH3 significantly decreased PD-L1 expression (75% and 34% reduction, respectively) with cell proliferation promotion. In conclusion, differences in MSH6/2 and PD-L1 expressions of SCAs, NCAs, and PIT1-lineage PAs from those of GAs appear to contribute to their clinically aggressive characteristics, such as more proliferation and invasiveness.

Aggressive pituitary tumors in the young and elderly.

Aggressive pituitary tumors (APTs) represent rare pituitary adenomas (PAs) with local invasion of surrounding tissues, increased risk for multiple recurrence, rapid tumor growth, or resistance to standard therapies. The most common APTs in children and adolescents are giant prolactinomas and somatotropinomas. Few cases of Crooke's cell adenomas, silent corticotroph adenomas and pituitary carcinomas havealso been reported in the literature. Pediatric patients with APTs have higher risk of harboring germline genetic defects, most commonly in the MEN1 and AIP genes. Since certain genetic defects confer a more aggressive behaviorto PAs, genetic testing should be considered in tumors with young onset and positive family history. The management of pediatric APTs involves usually acombination of standard therapies (surgical, medical, radiation). Newer agents, such as temozolomide, have been used in few cases of pediatric pituitary tumors with promising results. In the elderly, PAs are more commonly non-functioning. Their management often poses dilemmas given the coexistence of age-related comorbidities. However, standard surgical treatment and temozolomide seem to be safe and well tolerated in elderly patients.

Clinicopathological analysis of 250 cases of pituitary adenoma under the new WHO classification.

Pituitary adenomas (PAs) are a common subtype of intracranial tumors. The aim of the present study was to analyse the clinical and pathological features of different types of pituitary adenomas (PAs) according to the 2017 World Health Organisation Endocrine Organ Tumor Classification guidelines. The clinical data of 250 patients with PAs were collected and analysed. Differences in the incidence of invasion, recurrence and apoplexy in patients between high- and low-risk PAs were compared, as were differences in the Ki-67 index between invasive and non-invasive PAs and between recurrent PAs and non-recurrent PAs. Of the 250 cases, 45 cases were diagnosed as somatotroph adenomas, 26 cases as lactotroph adenomas, 1 case as thyrotroph adenoma, 61 cases as corticotroph adenomas, 93 cases as gonadotropin adenomas, 15 cases as null cell adenomas and 9 cases as plurihormonal adenomas. There were 5 types of high-risk pituitary adenoma identified: 17 cases of sparsely granulated somatotroph adenoma, 11 cases of lactotroph adenoma in men, 3 cases of plurihormonal PIT-1 positive adenoma and 42 cases of silent corticotroph adenoma. Crooke's cell adenoma was not identified. High-risk PAs had significantly higher rates of invasion, recurrence and apoplexy compared with that in low-risk types (P<0.001). Invasive PAs had a significantly higher Ki-67 index compared with that in non-invasive PAs (3.5±1.8 vs. 2.8±1.3; P<0.01). Recurrent PAs had a significantly higher Ki-67 index compared with that in non-recurrent PAs (3.9±1.9 vs. 2.8±1.3; P<0.001). According to the 2017 classification criteria, patients most frequently had gonadotrophin cell adenomas, followed by corticotroph adenomas and the proportion of null cell adenomas was reduced. Differences were noted in the proliferation, recurrence and apoplexy characteristics of high-risk PAs and low-risk PAs. The invasion and recurrence of PAs were found to be related to the Ki-67 index.

USP8 mutations in corticotroph adenomas determine a distinct gene expression profile irrespective of functional tumour status.

Pituitary corticotroph adenomas commonly cause Cushing's disease (CD) but part of these tumours are hormonally inactive (silent corticotroph adenomas, SCA). USP8 mutations are well-known driver mutations in corticotrophinomas. Differences in transcriptomic profiles between functioning and silent tumours or tumours with different USP8 status have not been investigated. Forty-eight patients (28 CD, 20 SCA) were screened for USP8 mutations with Sanger sequencing. Twenty-four patients were included in transcriptomic profiling with Ampliseq Transcriptome Human Gene Expression Core Panel. The entire patients group was included in qRT-PCR analysis of selected genes expression. Immunohistochemistry was used for visualization of selected protein. We found USP8 mutation in 15 patients with CD and 4 SCAs. USP8 mutations determine molecular profile of the tumours as showed by hierarchical clustering and identification of 1648 genes differentially expressed in USP8-mutated and USP8-wild-type tumours. Mutations affect many molecular pathways as observed in Gene Set Enrichment analysis. USP8-mutated adenomas showed higher level of POMC, CDC25A, MAPK4 but lower level of CCND2, CDK6, CDKN1B than USP8-wt tumours. Eighty-seven genes differentially expressed between CD-related adenomas and SCAs were found, including those involved in cell signalling (GLI2, DLC1, TBX2, RASSF6), cell adhesion (GJA1, CDH6), ion transport (KCNN4, KCNJ5) and GABA signalling (GABBR2, GABRD). USP8 mutations occur in functioning and silent corticotrophinomas. They have pleiotropic effect, not limited to EGFR signalling, and affect expression levels of many genes involved in different pathways. Expression of GABA-related genes GABBR2, GNAL, GABARD and KCNJ5 correspond to functional status of the tumours.

Predictive modeling for pituitary adenomas: single center experience in 501 consecutive patients.

Personalized postoperative management of patients with pituitary adenomas requires an early risk stratification system. We reviewed 501 cases operated between 10/27/2011 and 5/5/2016 by a single neurosurgeon. We determined biochemical remission and tumor resection at 3months, and biochemical recurrence, tumor recurrence, radiation and reoperation during follow-up. We considered age, gender, tumor diameter, cavernous sinus invasion (CSI) by MRI, diagnostic category (clinical, biochemical and immunohistochemical), and proliferation markers in a Cox proportional hazards model. We built predictive models with the significant parameters and used Kaplan-Meier survival curves for time-dependent analyses. The 501 cases comprised 141 functional and 360 nonfunctional adenomas. Tumor diameter, CSI, and ki-67 index predicted long-term events. Model 1 (CSI, diameter ≥ 2.9cm and ki-67 > 3%) identified 18 (3.6%) adenomas and predicted persistent hypersecretory syndrome and residual tumor with 98.7% specificity (OR 8.6; CI 3.0-24.7). Model 2 (ki-67 > 3% and CSI) identified 48 (9.6%) adenomas and had 93.1% specificity (OR 3.3; CI 1.8-6.0). Model 3 (ki-67 > 3%, mitoses and p53, former "atypical" adenoma) identified 26 (5.2%) adenomas and had 96.0% specificity (OR 2.3; CI 1.0-5.0). Model 1 best predicted the long-term event-free survival and was strengthened when Knosp 3-4 CSI grades were used. Model 2 better identified the smaller adenomas at risk. Among the WHO 2017 special PA subtypes, patients with silent corticotroph adenoma had a lower event-free survival than ACTH-negative nonfunctional adenomas. Use of CSI, ki-67 and tumor diameter in prediction models facilitates tailored surveillance and management of patients with pituitary adenomas.

Pathway enrichment analysis in functioning and silent corticotroph pituitary adenomas reveals mechanisms to explain their distinct clinical behaviour

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

MON-469 Pituitary Corticotroph Lesions: Clinical, Biochemical, and Pathological Characterization of Cushing Disease, Silent Corticotroph Adenomas, and Corticotroph Hyperplasia

Pituitary adenomas with positive ACTH staining are derived from the corticotroph lineage. Most corticotroph adenomas are small and secrete ACTH, causing a form of hypercortisolism known as Cushing disease (CD); however, a subset do not secrete ACTH and are referred to as silent corticotroph adenomas (SCA). Rarely, hypercortisolemic patients who undergo surgery are diagnosed with the ill-defined entity of corticotroph hyperplasia (CH). In order to better define CH and compare the clinical, laboratory, and imaging parameters of CD, SCA, and CH, comprehensive chart review was performed for all patients at our institution within the past ten years who underwent transsphenoidal surgery for a pituitary mass showing diffuse ACTH immunostaining in lesional tissue. All cases were re-reviewed by an experienced neuropathologist to confirm the diagnoses. Patients with clinical and biochemical evidence of ACTH-dependent hypercortisolemia and an ACTH-positive adenoma were classified as CD (n=59). Patients without hypercortisolemia but with ACTH-staining adenomas were classified as SCA (n=32). Patients clinically suspected of having Cushing disease whose surgical specimen did not show adenoma but consisted only of abnormally expanded acini with ACTH-positive cells were classified as CH (n=13). Average (± SD) pre-operative cortisol (mcg/dL)/ ACTH (pg/mL) measurements were: CD 23.7±8.1 / 66.4±40.1; SCA 12.7±6.2 / 44.4±38.0; CH 24.5±5.9 / 63.8±35.1. SCA patients had larger tumors and presented with more symptoms of compression whereas both CD and CH patients presented with characteristic features of hypercortisolism: weight gain, hypertension, hirsutism, and skin changes (p<0.05 compared to SCA). Compared to CD patients, CH patients more frequently exhibited mood changes (p=0.007) and cognitive dysfunction (p=0.002). CH patients without prior pituitary surgery on average had a greater absolute number of negative late-night salivary cortisol results than CD patients (p=0.006). Of the patients with adequate follow-up, CH patients had higher cortisol levels 6 months post-operatively (p=0.007). Most patients with CH (8/13, 61.5%) had discrete lesions identified on pre-operative MRI. CD patients were more likely to have a higher MIB-1 proliferative index than those of CH patients (CD: 2.8±3.7, CH: 0.4±0.2, p=0.029). In conclusion, SCAs are more likely to cause symptoms of compression, while CD and CH cause symptoms related to hypercortisolism. There may be subtle differences between CD and CH patients, but both groups manifest with ACTH-dependent hypercortisolism and can be nearly indistinguishable pre-operatively. The difference in MIB-1 indices suggests that CH may represent a reactive or pre-neoplastic condition as opposed to undersampled adenoma. Further studies are needed to better understand the pathophysiology of corticotroph cell hyperplasia and its relation to CD.

MON-412 Subclinical Cushing's Disease and the Importance of Broad Differential Diagnoses

Introduction: Cushing disease is the most common cause of endogenous Cushing syndrome, and if undiagnosed, carries significant morbidity including diabetes, obesity, infertility, and osteoporosis. Physical exam findings commonly seen include violaceous abdominal striae, supraclavicular fat pads, facial plethora, and proximal muscle weakness. Here, we discuss a case of a rare presentation of Cushing disease in a patient whose chief complaint was fatigue with none of the aforementioned physical manifestations. Case: A 43 year old female with a medical history of multinodular goiter status post hemithyroidectomy presented with persistent fatigue and weight gain over a one year period. Physical exam revealed normal body habitus, no thyroid nodules, no supraclavicular fat pad, abdominal striae, or proximal muscle weakness. Thyroid studies were normal, and despite lifestyle modifications, the patient's symptoms persisted. Laboratory workup revealed elevated midnight salivary cortisol levels, an elevated 24 hour urine free cortisol measurement, and on dexamethasone suppression testing, elevated ACTH levels, confirming Cushing disease. Pituitary MRI was significant for pituitary macroadenoma with cystic changes measuring 1.1x1.9cm and mild compression of the optic chiasm. The patient was transferred for surgical resection, where pathology was consistent with an ACTH-secreting adenoma. Discussion: Subclinical Cushing's disease is defined by an adrenocorticotrophic hormone (ACTH)-induced mild hypercortisolism without typical features of Cushing's disease. In a 2016 cohort study, the prevalence of subclinical and silent corticotroph adenomas was approximately 40%, making it imperative for practitioners to have a broad differential when evaluating patients with non-specific complaints. Additional studies show that clinically silent adenomas (adenomas with normal cortisol secretion and ACTH-immunopositive staining without autonomous ACTH secretion) have the risk of progressing to Cushing's disease, thereby carrying the risk of increased morbidity secondary to the metabolic derangements due to hypercortisolism. Finally, should surgical resection be warranted, the size of the adenoma has been associated not only with the level of difficulty of surgical resection, but also with the risk of recurrence. Ultimately, it behooves the medical community to obtain detailed histories, conduct thorough physical, and maintain broad differentials of rare conditions to allow for better screening.

MON-406 Two Cases of Aggressive Corticotroph Pituitary Tumors Treated with Capecitabine and Temozolomide

Introduction: Aggressive corticotroph tumors exhibit continued growth despite multimodal therapy, including surgeries, radiotherapy and/or medical treatment. Temozolomide (TMZ), an oral alkylating agent, has been used to treat aggressive pituitary tumors; however, most patients only showed a partial response. Recent evidence suggests that TMZ administered with capecitabine (CAP) is effective and safe in treating patients with aggressive corticotroph tumors resistant to conventional therapy. Here, we present two patients with recurrence of aggressive corticotroph pituitary tumors after surgery and radiation therapy and good response to treatment with CAP and TMZ (CAPTEM). Clinical presentation: Case 1: A 54-year-old man presented with right-sided headache and dizziness. Examination revealed palsies of the right 3rd, 4th, 5th and 6th cranial nerves. MRI confirmed a 3.6 x 3.7 x 3.5 cm sellar/suprasellar mass with right cavernous sinus invasion, chiasmal compression and clival replacement. He had transsphenoidal surgery and pathology showed a sparsely granulated ACTH adenoma with necrosis. With evidence of hypopituitarism, he was placed on prednisone, levothyroxine and testosterone. He also received stereotactic radiotherapy to manage his residual adenoma. Three years later, he presented with new onset neck pain and imaging studies showed leptomeningeal disease and biopsy confirmed ACTH adenoma. He was treated with CAPTEM for one year which resulted in clinical remission with marked radiological improvement, and persistent tumor control 20 months after cessation of therapy. Case 2: A 48 year-old man seen post transsphenoidal surgery for management of his recurrent silent corticotroph adenoma. He presented at age 21 with vision loss and had his first craniotomy. At age 31, he had repeat craniotomy for tumor recurrence that was followed by radiation therapy. With documented hypopituitarism, he has been on hydrocortisone, levothyroxine and testosterone. Although he has been legally blind, he did notice further vision loss prior to his transsphenoidal surgery. MR sella showed a 3.0 x 3.6 x 2.5 cm sellar mass infiltrating the clivus, sphenoid sinus, both cavernous sinuses and extending and compressing the optic chiasm. Even though there was good debulkment of the sellar mass, rapid tumor regrowth was noted on follow up MRI 18 months later. As the neurosurgeon did not feel that the patient would benefit from further surgery, he was treated with a year of CAPTEM. This led to significant tumor shrinkage with no tumor regrowth four months after completion of therapy. Conclusion: Our cases represent the sixth and seventh cases of CAPTEM-treated aggressive corticotroph tumors with good response to therapy. TMZ in combination with CAP seems to be promising in the management of patients with aggressive corticotroph pituitary tumors, and potentially other aggressive pituitary adenomas.

Clinical Significance of Radical Surgery in the Treatment of Silent Corticotroph Adenoma.

ObjectiveSilent corticotroph adenomas (SCA) are endocrine-inactive pituitary adenomas with positive immunohistochemistry staining for adrenocorticotropic hormone (ACTH). We investigated whether SCA-associated clinical profiles were more aggressive than hormonally negative adenomas (HNA). MethodsAmong 627 patients with pathologically proven endocrine-inactive pituitary adenomas between 2004 and 2013, positive immunohistochemistry revealed 55 SCAs and 411 HNAs. Surgical outcomes and radiological and endocrinological characteristics were compared. ResultsStrong female predominance was observed in the SCA group (p<0.001). Cavernous sinus invasion was identified in 22 (40%) SCA patients and 72 (17.6%) HNA patients (p<0.001). There were no differences in ACTH or cortisol levels between the two groups. The incidence of preoperative hypopituitarism and postoperative hormonal outcome did not differ between two groups. Total resection was achieved in 35 patients (63.7%) with SCA and 332 patients (80.8%) with HNA (p=0.007). When tumors were completely removed, recurrence rates were not statistically different between two groups (p=0.60). When complete resection was not achieved, tumors regrew from these remnants in seven patients (35.0%) with SCA and 12 patients (15.2%) with HNA (p=0.05). ConclusionTotal surgical resection for SCA is often challenging as these tumors frequently invade a cavernous sinus. Early remnant tumor intervention is justified, because untreated residual pituitary tumors regrow when patients were followed up for a long time. Prophylactic radiotherapy is not warranted for completely resected SCAs as tumor recurrence is uncommon.

Recurrence in silent corticotroph adenomas after primary treatment: A systematic review and meta-analysis.

2017 WHO Classification of Pituitary Tumors grades silent corticotroph adenomas (SCAs) as "high-risk adenomas" due to their aggressive clinical behavior (high probability of recurrence). However, studies comparing recurrence rates of SCAs with other non-functioning pituitary adenoma (NFPAs) subtypes have provided conflicting results. Estimate recurrence rates of SCAs after primary treatment (surgery±radiotherapy) and recurrence rate ratios (RRR) between SCAs and other NFPA subtypes. Systematic review of published literature reporting on outcomes of SCAs up to October 31, 2017 was conducted. Recurrence rates, RRRs, 95% confidence intervals (CIs) were estimated from each study and pooled using random effects meta-analysis model. For determination of SCAs recurrence rates, 14 studies (low risk of bias, 297 patients) were selected; recurrence rate was 5.96 (95% CI, 4.3-7.84) per 100 person-years. Based on studies with mean follow-up <5 or ≥5 years, 25% (cumulative incidence 0.25; 95% CI, 0.13-0.38) and 31% (cumulative incidence 0.31; 95% CI, 0.23-0.40) of SCAs had recurrence, respectively. Recurrence rates after surgery or surgery+radiotherapy were 5.41 (95% CI, 3.28-7.96) and 4.88 (95% CI, 0.67-11.54) cases per 100 person-years, respectively. Analysis of 10 eligible studies (moderate risk of bias, 244 SCAs, 1622 NFPAs) showed no significant RRR (1.44; 95% CI, 0.9-2.33, p=0.130) between the groups. Focus on tumors treated solely by surgery also revealed no significant RRR (1.17; 95% CI, 0.79-1.75, p=0.429). Based on studies with mean follow-up ≥5 years, 31% of SCAs have recurrence. No evidence supporting higher recurrence risk of SCAs compared with other NFPA subtypes was found.

Clinical outcomes in male patients with lactotroph adenomas who required pituitary surgery: a retrospective single center study.

Lactotroph adenomas (LA) are the most frequently encountered pituitary tumors. Although more frequently observed in women, LAs in men were recently included in a more aggressive category regardless of histological grading, by the WHO. We aimed to perform a rigorous retrospective review of a single center's pre-operative evaluation, patient characteristics and outcomes of male LAs patients requiring pituitary surgery. A retrospective review, over 11 years, of patients who underwent resection of a pituitary adenoma at a single center was conducted. Predictors of persistent disease in male LAs patients along with a comparison to predictors of silent corticotroph adenomas (SCAs) patients who also underwent surgery at the center was also conducted. Thirty-one male patients with LAs were identified. When compared to SCAs patients, LAs male patients were younger (41 vs. 50years of age, p = 0.01). Men with LAs had more invasive tumors (75% vs. 44.7% p = 0.02). More LAs in men had residual tumor after surgery than patients with SCA (92.6% vs. 42.1%, p < 0.001). Male patients with LAs and patients with SCA had similar rates of requiring additional surgery (28.9% vs. 24.1%, p = NS) and radiation therapy (18.4% vs. 19.4%, p = NS). High rates of DA resistance, invasive tumors and postoperative residual disease in male patients with LA who required surgery are shown. Surgery improved optic chiasm compression, PRL level and central hypogonadism but, not surprisingly, failed to normalize other pituitary hormones and/or eliminate need for DA therapy.

Clinical Parameters to Distinguish Silent Corticotroph Adenomas from Other Nonfunctioning Pituitary Adenomas

It is difficult to distinguish silent corticotroph adenomas (SCAs) from other nonfunctioning pituitary adenomas (NFPAs) preoperatively. This study aimed to determine the preoperative clinical parameters associated with SCAs. This was a retrospective single-center study of patients who underwent surgery for NFPAs during 2011-2016 in our tertiary hospital and who had preoperative combined pituitary function test (CPFT) and immunohistochemical staining results available. After we excluded patients with increased 24-hour urinary free cortisol to preclude overt Cushing's disease, 341 patients were finally enrolled. The medical records, including the CPFT and immunohistochemistry results, of the patients were reviewed. The age and tumor size were similar between patients with SCAs and other NFPAs. The SCA group had a greater proportion of women (89.2% vs. 57.6%, P < 0.001), cavernous sinus invasion (35.1% vs. 20.7%, P= 0.047), and intratumoral hemorrhage on preoperative sella magnetic resonance imaging (32.4% vs. 9.2%, P < 0.001) compared with the NFPA group. In the preoperative CPFT, the cortisol response was not significantly different between groups. However, the peak adrenocorticotropic hormone (ACTH) (67.80 ± 49.83 vs. 85.67 ± 78.97 pg/mL, P= 0.061) tended to be lower, and the ΔACTH (53.71 ± 50.14 vs. 72.67 ± 75.82 pg/mL, P= 0.046) was significantly lower in SCAs. After we excluded patients with preoperative hypopituitarism caused by mass effects, the peak ACTH (69.39 ± 39.45 vs. 119.75 ± 89.84 pg/mL, P= 0.001) and ΔACTH (58.58 ± 36.51 vs. 107.66 ± 86.05 pg/mL, P= 0.001) were significantly lower in SCAs than in other NFPAs. Female sex, cavernous sinus invasion, intratumoral hemorrhage on sella magnetic resonance imaging, and decreased ACTH response in the CPFT are independent indicators of SCAs.